Process for manufacturing a stationary state of crystalline polymer of a biodegradable polymer matrix carrying an active substance and a polymer matrix produced thereby

Abstract

A method for manufacturing a stationary state of polymer crystallinity of an active substance charged polylactide matrix for a stent, comprising the steps of: preparing the active substance charged polylactide matrix containing (a) a polylactide in amorphous or semicrystalline modification or with amorphous domains, and (b) at least one active substance on a surface or in a cavity of the stent communicating with the surface; and heating of the active substance charged polylactide matrix to a temperature ranging from TG-20° C. to TS-10° C., where TG represents a glass transition temperature and TS a melting temperature of the crystallites of the polylactide.

Description

FIELD OF THE INVENTION[0001]The invention relates to a method for the manufacture of a stationary state of polymer crystallinity of an active substance charged biodegradable polylactide matrix, a polylactide matrix obtained according to the method and an implant with a coating from the polylactide matrix.BACKGROUND OF THE INVENTION[0002]Pharmaceutical active substances are frequently incorporated in a matrix formed from a biodegradable polymer for intracorporeal administration. The polymer matrix therefore represents an active substance depot (slow release) which is inserted / implanted in the body of the patient to be treated by surgery, and there gradually releases the active substance. The polymer matrix then degrades so that no further surgery is required for extraction of the polymer matrix. For example, the active substance charged polymer matrix may be introduced directly into the vascular system of a patient as an active substance depot or may be used to charge a cavity which ...

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Benefits of technology

[0005]The one feature of this invention is therefore to provide a method with which the above-mentioned disadvantages of the state of the art can be overcome and improved storage stability of the polylactide matrix can be achieved in terms of its elution characteristic.

[0009]The invention is based on the knowledge that tempering the active substance charged polylactide matrix within the temperature limits mentioned eliminates the risk of the recrystallisation of frozen, crystallisable amorphous polymer domains of the polymer matrix. In other words, a stationary state of polymer crystallinity is produced by tempering without this resulting in thermal degradation of the polymer matrix. Our own studies have shown that a suitably tempered polymer matrix is storage stable in terms of its elution characteristic, i.e., the elution characteristic was disassociated from the phenomenon of recrystallisation of frozen, crystallisable amorphous polymer domains.

[0010]Surprisingly it has been shown that the tempering according to the invention also results in an acceleration of the active substance elution, which is advantageous when combined with stent coating systems, because in this application a locally high active substance dose immediately after implantation is desirable. Normally an inhibition of the diffusive processes, or a deceleration in active substance elusion might be expected as the crystallinity of the matrix increases, as also described for example in WO 2005 / 004945. The opposite effect of accelerated release now established is probably due to the active substance enrichment on the crystalline polymer domains additionally produced by tempering. This phase segregation results in increased active substance concentration in the amorphous domains of the polylactide matrix compared to its crystalline domains.

[0018]Another method variant which can also be carried out in conjunction with the previously mentioned preferred variant of the invention provides that the preparation of the polylactide matrix according to step (i) is carried out by applying a finely dispersed aerosol to a surface of a stent by means of a rotary atomiser. Homogeneous coatings can be produced extremely easily by this method. Preferably the average droplet size of the aerosol in this case is <70 μm, and in particular in the range of 5 to 25 μm. This avoids adhesion of the individual stent struts.

[0021]A second aspect of the invention lies in the preparation of a stent with a polylactide matrix which can be manufactured by the method previously described. The tempering results in a modification change in the active substance charged polylactide matrix, which is demonstrable in the product and ultimately improves storage stability and reduces variance in the elution characteristic.

Problems solved by technology

In other words, a stationary state of polymer crystallinity is produced by tempering without this resulting in thermal degradation of the polymer matrix.

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